High levels of comorbidity have been observed between nicotine dependence and persistent pain conditions. There are also suggestions that nicotine dependence may complicate the presentation and outcomes of patients experiencing persistent pain, already a condition that is both difficult to treat and can be self- perpetuating. Experimental evidence shows that nicotine has effects on pain regulatory mechanisms. The effects of the interaction between nicotine dependence and chronic pain are however poorly understood at both neurobiological and phenotypic levels, particularly in humans. The present proposal is concerned with individual variations in the function of neurochemical mechanisms implicated in the pathophysiology of both chronic pain and nicotine dependence and how they impact on the individual characteristics of both disorders. It is proposed to examine the function of endogenous opioid and dopamine neurotransmission, systems involved in the reinforcing effects of nicotine in the CNS, but also known to be dysregulated in chronic pain conditions. We propose to first characterize the effects of nicotine dependence on the responses of dopamine and opioid systems to sustained experimental pain, by comparing them to those of non-smoker controls. Neurobiological responses will then be related to pain psychophysics and measures related to nicotine dependence (e.g., craving). Similar studies and analyses are proposed in samples of chronic low back pain patients, nicotine dependent or non-smokers. We will employ the selective radiotracers [11C]carfentanil and [11C]raclopride and positron emission tomography for the non-invasive quantification of dopamine D2/3 and 5- opioid receptors. Baseline, pain expectation and pain responses will be quantified and examined against psychophysical characteristics across the four matched volunteer groups proposed: non-smoker and nicotine dependent controls, chronic low back pain non-smokers and nicotine dependent. At the completion of these studies we will be able to determine how nicotine dependence modifies pain responses in humans, and how pain, both clinical and experimental, modifies neurobiological and phenotypic elements of this addiction (e.g., craving). In addition, the interaction between an existing persistent painful condition and nicotine dependence will be examined at the neural function level and related to the individual clinical and experimental pain experience and measures of nicotine dependence. Both nicotine dependence and chronic pain are self- perpetuating conditions with high comorbidity. The studies proposed will clarify their points of interaction at neurobiological and psychophysical levels, providing much needed information for the understanding of individual variations in patient presentation and clinical courses. This information would ultimately guide individualized treatment strategies by providing a neurobiological framework for their development.